Steroid receptors (SRs) are hormone-activated transcription factors controlling tissues-specific gene expression and therapeutically important physiologies. In their inactive states, these receptors are known to form complexes with the chaperone Hsp90 which in turn can be bound by one of four tetratricopeptide repeat (TPR) proteins: FKBP52, FKBP51, Cyp40 and PP5. This fact means that SRs exists in distinct heteromeric complexes defined by TPR protein content. If these distinct complexes exist, they must have distinct functions. Yet we know almost nothing of these differential functions. We now have new evidence to suggest that TPR proteins serve to regulate distinct stages of SR signaling within a cell, as well as tissue specific responses to steroids. We base these conclusions on key observations from our laboratories. We have uncovered a new first step in hormonal activation of the glucocorticoid receptor (GR) that involves a coordinated exchange of FKBP51 for FKBP52 within GR complexes. This TPR exchange is the signal that tells GR complexes to recruit the transport protein dynein and move to the nucleus. We have also determined that FKBP52, PP5 and FKBP51 have hierarchical effects on the hormone-binding function of the GR, and that Cyp40 can regulate both GR protein levels and cause it to become nuclear. Last but not least, we have generated FKBP52 knockout mice that manifest female sterility. Further characterization has revealed the infertility to result from inactivity in the uterus by the PR-A progesterone receptor isoform, leading to a failure of implantation. Interestingly, both the PR-B isoform and the estrogen receptor in uterus tissue were unaffected by loss of FKBP52. Thus, it is now clear that distinct TPRs will have both receptor- and tissue-specific impacts on physiology. With this in mind, the goals of this proposal are to further define the roles of TPR proteins in GR and PR functions under cell-free and tissue culture conditions, followed by testing of mechanisms in select physiological responses using FKBP52 and FKBP51 knockout animals. A better understanding of differential TPR protein effects on both GR and PR could now form the basis for new therapeutic strategies targeting fertility and other physiologies.